Microbubble contrast agents are used to enhance ultrasound images of the vascular space, as non-contrast ultrasound is only very weakly sensitive to blood flow in small vessels. Currently, microbubbles are approved clinically for left ventricular border enhancement in sub-optimal echocardiography, and are used pre-clinically for perfusion imaging and molecular imaging of diseased tissue. However, due to their size, microbubbles cannot extravasate into the tissue and therefore cannot be used as extravascular contrast agents. Recently, we have developed nanodroplet perfluorohexane emulsions that can extravasate out of the vasculature. Surprisingly, despite their boiling point (bp = 610 C) these droplets were found to vaporize and form gas deposits in tissue. Based upon this knowledge, we have preliminarily formed liquid perfluorocarbon nanodroplets which can be turned into microbubbles with acoustic energy (referred to as "pro-bubbles"). For this proposal, we hypothesize that if we add a known amount of perfluorohexane to a pro-bubble, we can create a particle which can extravasate, and then can be activated by ultrasound energy to form a micron-sized gas bubble. A targeted pro-bubble which can extravasate into the extravascular space/tissue will be able to accumulate at diseased tissue such as micrometastases, which would not normally be accessible by microbubbles. After extravasation and localization at a target site, we can use ultrasound to activate the "pro- bubble" into a microbubble of defined size for high-sensitivity ultrasound imaging. PUBLIC HEALTH RELEVANCE: Microbubble contrast agents are used with ultrasound to image for disease and abnormalities inside the vasculature. However, because of their size, microbubbles cannot diffuse outside the vessels to image tissue. We propose the development of a targeted liquid drop or "pro-bubble" which is small enough to diffuse outside the vasculature and target diseased tissue. Once targeted to diseased tissue, the pro-bubble can be converted to a bubble by ultrasound where it can now be imaged. This pro-bubble could allow clinicians to image very small metastatic tumors that heretofore may not be identified and could eventually be used to destroy the small tumors using non-invasive ultrasound techniques. This new and innovative methodology could potentially advance early detection and treatment of cancer.